Biological and Phytochemical Screening of Plants

Summary A phytochemical investigation of the plant Vinca rosea Linn. has demonstrated that a number of alkaloidal substances can be obtained with antitumor activity. Over 30 alkaloids have been obtained, of which four—vinblastine, vinleurosine, vincristine, and vinrosidine—are known definitely to be active. Chemically these compounds are closely related to one another and to two monomeric alkaloids, vindoline and catharanthine. The structure of these latter two compounds has been determined, and partial structures for the biologically active alkaloids have been proposed. They represent a new class of large complex dimeric alkaloids containing both indole and dihydroindole moieties. Experimentally, a strain-specific, transplantable, acute, lymphocytic leukemia (P-1534) carried in DBA/2 mice served as a bioassay for obtaining these compounds and for predicting their clinical activity. Vinblastine, vincristine, and vinrosidine are capable of prolonging and/or “curing” mice of the P-1534 leukemia even when therapy is delayed until a near-terminal state of generalized disease. Resistance to an additional challenge of leukemic cells has been observed in these “cured” animals. Parenteral administration of vincristine has been demonstrated to “cure” mice given intracranial implants of the P-1534. The experimental tumor spectrum and toxicological studies are presented and discussed. Biochemical studies performed to date do not reveal any effect on cellular respiration, glycolysis, protein or nucleic acid synthesis. The mechanisms of action of these compounds, which may differ within the group as well as from those of other known agents, remain to be determined. Only two of these compounds, vinblastine and vincristine, have received extensive clinical evaluation. In spite of their close similarity, chemically, a somewhat different group of human neoplasms responds to these compounds, and there has been a singular lack of cross-resistance between these two drugs and any other oncolytic drug now in wide use. Vinblastine has proved effective in chorioepithelioma, Hodgkin9s disease, and other lymphomas, and a number of beneficial results have been obtained in carcinoma of the breast and bronchus. In addition, there have been smaller numbers of a variety of other neoplasias reported as responding to this compound. Vincristine has been striking in its ability to induce complete hematological remission of the acute leukemias of childhood, both lymphocytic and myelogenous in type. Responses have also been reported in a number of other malignancies. The problems and obstacles encountered in obtaining a full realization of the clinical efficacy of these new types of oncolytic compounds are discussed in addition to areas of clinical application other than those previously reported.

https://cancerres.aacrjournals.org/content/canres/23/8_Part_1/1390.full.pdf

The Vinca Alkaloids: A New Class of Oncolytic Agents

Taxanes, microtubules and chemoresistant breast cancer.

Natural compounds that target microtubules and disrupt the normal function of the mitotic spindle have proven to be one of the best classes of cancer chemotherapeutic drugs available in clinics to date. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell-cycle progression at mitosis and subsequently leading to cell death. Our improved understanding of tumor biology and our continued appreciation for what the microtubule targeting agents (MTAs) can do have helped pave the way for a new era in the treatment of cancer. The effectiveness of these agents for cancer therapy has been impaired, however, by various side effects and drug resistance. Several new MTAs have shown potent activity against the proliferation of various cancer cells, including resistance to the existing MTAs. Sustained investigation of the mechanisms of action of MTAs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance could provide more effective therapeutic options for patients with cancer. This review focuses on the successful cancer chemotherapy from natural compounds in clinical settings and the challenges that may abort their usefulness. Mol Cancer Ther; 13(2); 275–84. ©2014 AACR .

https://mct.aacrjournals.org/content/molcanther/13/2/275.full.pdf

Targeting Microtubules by Natural Agents for Cancer Therapy

Five years' experience with the chemotherapy of metastatic choriocarcinoma and related trophoblastic tumors in women

Summary The experimental activity of a new clinically confirmed antitumor compound, Vincaleukoblastine (C46H58O9N4), (VLB) as the sulfate has been described. Greatest activity was seen against the P-1534 acute lymphocytic leukemia in DBA/2 mice. Late as well as early stages of this leukemia were significantly affected by this compound. No synergistic or additive effects have been observed in combination therapy with other antitumor compounds. A second indole-indoline alkaloid, leurosine, isomeric with VLB, has also been obtained from Vinca rosea Linn, with similar demonstrable experimental antitumor activity. Two other alkaloids, vindoline (C25H32O2) and catharanthine (C21H24O2N2), also obtained from Vinca rosea, were devoid of antitumor activity singly or in equimolar concentrations, but have been postulated as the biogenetic precursors of VLB and leurosine. Preliminary studies in vitro demonstrated that certain compounds were capable of reversing the growth-inhibitory activity of VLB against human monocytic leukemia cells. These compounds were coenzyme A, aspartic acid, tryptophan, α-ketoglutaric acid, ornithine, citrulline, arginine, and glutamic acid. VLB and leurosine are representatives of a new class of clinically active antitumor compounds which may interfere with the cellular metabolic pathways leading from glutamic acid to urea, and from glutamic acid to the citric acid cycle.

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Janet Vlantis

Papers

Antitumor principles derived from Vinca rosea Linn. I. Vincaleukoblastine and leurosine.